A novel mutation in SMARCB1 associated with adult Coffin-Siris syndrome and meningioma

SMARCB1 encodes a core subunit of the SWI/SNF chromatin remodeling complex, which plays a crucial role in the regulation of gene expression. Germline mutations in the SMARCB1 gene have been linked to early childhood Coffin-Siris syndrome type 3 (CSS3), a rare congenital malformation syndrome characterized by severe developmental delay and intellectual disability. In this study, we report two adult CSS3 patients with novel missense SMARCB1 mutation (c.1091A>C, p.Lys364Thr) identified through whole exome sequencing (WES). Both two patients exhibited selective difficulties in verbal learning and language delay. Additionally, the development of meningioma was confirmed in one of the patients. Mechanistic studies indicate that this missense mutation may abnormally activates the expression of MAPK14, a gene implicated in the pathogenesis of tumor progression and neurodevelopmental disorders. This is the first reported case of a germline mutation in SMARCB1 gene associated with both CSS3 and meningioma, thereby expanding the phenotypic spectrum of SMARCB1-related neurodevelopmental disorders. To investigate the impact of the missense mutation (c.1091A>C, p.Lys364Thr) on the function of the SMARCB1 protein, we established wild-type and mutant SMARCB1 overexpression IOMM-Lee cell lines via lentiviral transfection. Subsequently, we examined the effects of this mutation through transcriptome analysis, focusing on their influence on gene expression profiles.

SMARCB1基因编码SWI/SNF染色质重塑复合物（SWI/SNF chromatin remodeling complex）的核心亚基，该复合物在基因表达调控中发挥关键作用。SMARCB1基因的生殖系突变与儿童早期3型科芬-西里斯综合征（Coffin-Siris syndrome type 3, CSS3）相关，该疾病是一种以严重发育迟缓与智力残疾为特征的罕见先天性畸形综合征。本研究报道了2例经全外显子组测序（whole exome sequencing, WES）鉴定出携带新型错义SMARCB1突变（c.1091A>C, p.Lys364Thr）的成人CSS3患者。两名患者均表现出言语学习选择性障碍与语言发育迟缓。此外，其中1例患者被确诊患有脑膜瘤。机制研究表明，该错义突变可异常激活丝裂原活化蛋白激酶14（MAPK14）的表达，该基因与肿瘤进展及神经发育障碍的发病机制相关。本研究首次报道了同时伴随CSS3与脑膜瘤的SMARCB1基因生殖系突变病例，从而拓展了SMARCB1相关神经发育障碍的表型谱。为探究该错义突变（c.1091A>C, p.Lys364Thr）对SMARCB1蛋白功能的影响，我们通过慢病毒转染（lentiviral transfection）技术构建了过表达野生型与突变型SMARCB1的IOMM-Lee细胞系。随后，我们通过转录组分析（transcriptome analysis）检测了该突变的影响，重点关注其对基因表达谱的作用。